ADME

Question 1

Drug response (efficacy) and adverses lead to..

Answer 1

many drugs not completing clinical trials

Question 2

What percent of compounds entering Phase 2 fail prior to Phase 3?

Answer 2

66%

Question 3

Failure rate at Phase 3?

Answer 3

33%

Question 4

DD process is very costly, why important?

Answer 4

$1.8bn per NME, no adverses cause its withdrawal from market

Importance of thorough ADME testing (Paul et al., 2008)

Question 5

Importance of ADME

Answer 5

Need of in vitro studies to assess efficacy and safety of drugs metabolised by polymorphic enzymes and those inhibited by other drugs (D-D interactions)

Question 6

What percent in the US of hospital patients experience SADRs? How many die from SADRs?

Answer 6

6.2-6.7% have SADRs
5% die from SADRs
(Wilkie et al., 2007 & Wester et al., 2008)

Question 7

Contributing factors to ADME

Answer 7

Disease
Age
D-D interactions (number of patients being treated with multiple medications continues to increase) Huang et al., 2008
Environment (foodstuffs like grapefruit juice affects CYP3A4/2D6 and dietary supplements)
Compliance (~50% of schizophrenic patients fail to take drugs as perscribed)

Question 8

Thiopurine drugs

Answer 8

6-MP
6-TG
Azothioprine

Question 9

Thiopurine drugs are used for

Answer 9

Neoplastic disorders (acute lymphocytic leukaemia)
Autoimmune disorders
IBD
Organ transplants

Question 10

Major toxicity of thiopurine drugs

Answer 10

Myelosuppresion

Question 11

What is azothioprine converted to?

Answer 11

6-MP

Question 12

TPMT enzyme is responsible in part for what?

Answer 12

Methylation of 6-MP to the inactive metabolite 6-methyl MP

Question 13

What does methylation of 6-MP prevent?

Answer 13

Prevents 6-MP being activated to cytotoxic TGN nucleotides

Question 14

Cytotoxic TGN nucleotides…

Answer 14

TGMP
TGDP
TGTP

Question 15

What do cytotoxic TGN nucleotides do

Answer 15

Incorporate into DNA during S-phase

Inhibit GTP-binding protein Rac-1 - which regulates Rac/Vav pathway

Question 16

TPMT (thiopurine methyltransferase) is

Answer 16

A genetic polymorphism

Question 17

Prevalence of TPMT polymorphism

Answer 17

1 in 300 people are deficient for TPMT

National Centre for Biotechnology Information, 2012

Question 18

How many polymorphisms found for TPMT, and the most common?

Answer 18

> 30 polymorphisms
More common: TPMT3A and TPMT3C
Both point mutations

Question 19

Genetic variants mapping to TPMT region detemine what

Answer 19

Mapping at chromsome 6
Primary determinants of TPMT activity in humans
(Tamm et al., 2017)

Question 20

Why are TPMT*3A and 3C alleles non-functional

Answer 20

Affect protein activity by post-translational modification and increase protein degradation
(Tamm et al., 2017)

Question 21

TPMT degradation by ATP-dependent proteasome mediated pathway results in..

Answer 21

Loss of catalytic activity of the enzyme

Question 22

Patients treated with thiopurine drugs require what

Answer 22

Genotyped before being prescribed

Question 23

Irinotecan (Innocenti et al., 2004)

Answer 23

Used for metastatic colorectal cancer

Question 24

Side effects of irinotecan

Answer 24

Severe diarrhoea and neutropenia (abnormally low neutrophils)

Question 25

Percentage of patients with SADRs using irinotecan

Answer 25

20-35%

Question 26

Prevalence of fatal events during single-agent irinotecan treatment

Answer 26

5.3%

Question 27

Irinotecan activated by hydrolysis to..

Answer 27

SN-38

Question 28

What is SN-38?

Answer 28

A potent topoisomerase 1 inhibitor

Question 29

What inactivates SN-38?

Answer 29

UGT1A1 | Inactivated by biotransformation into SN-38 glucuronide

Question 30

UGT1A1 catalyses what?

Answer 30

Bilirubin glucuronidation | 5-8 repeats in the TATA box

Question 31

TA6 genotype prevalence

Answer 31

50% of population | Normal expression

Question 32

TA7 genotype associated with..

Answer 32

Classical Gilbert's syndrome | Common milk hyperbilirubinemia and decrease activity of the bilirubin uridine di-p glucuronosyltransferase

Question 33

TA7 geneotype prevalence

Answer 33

Up to 40% of population Results in decreased UGT1A1 expression Increase risk to toxicity

Question 34

Results of Innocenti et al 2004 show what percent of 7/7 homozygous patients develop grade 4 neutropenia

Answer 34

50% of 7/7 homozygous patients develop Grade 4 neutropenia

Question 35

What percent of 6/7 patients develop Grade 4 neutropenia?

Answer 35

12.5%

Question 36

What percent of 6/6 patients develop Grade 4 neutropenia?

Answer 36

0%

Question 37

Dosage and duration of patient treatment by Innocenti et al 2004

Answer 37

350mg/m^2 every 3 weeks

Question 38

Overall percentage of grade 4 neutropenia?

Answer 38

9.5%

Question 39

Grade 4 neutropenia highly correlated with..

Answer 39

TA indel genotype (promoter variant)

Question 40

What was TA7 allele a significant predictor of?

Answer 40

Severe toxicity

Question 41

-3156G>A promoter variant may be a better predictor of what?

Answer 41

UGT1A1 status than TA indel | Increase in SN-38 levels are systemically available when UGT1A1 is deficient

Question 42

Overall conclusion by Innocenti et al 2004

Answer 42

Irinotecan 350mg/m^2 is relatively safe in cancer patients with -3156GG genotype Should get a lower dose or an oxaliplatin-fluoropyrimidine regime

Question 43

Enzymes in CYP1-3 families show polymorphism, including

Answer 43

CYP2D6, 2C19

Question 44

2D6 shows highest polymorphic profile, why is that important?

Answer 44

Involved in metabolism of 25% of all clinical drugs | Oxidation reactions

Question 45

What is CYP2D6 required for?

Answer 45

Conversion of codeine into morphine in pain relief | Poor metabolisers will not get pain relief but ultrarapid metabolisers may receive significant toxicicty

Question 46

CYP2D6 required in treatment of breast cancer for..

Answer 46

Conversion of tamoxifen to endoxifen 100X greater affinity for ER Prevent/ treat breast cancer

Question 47

Role of pharmacogenomics in atypical medication for schizophrenic patients

Answer 47

Foster et al, 2007

Question 48

Problem with atypical medication for schizophrenic patients

Answer 48

``` Weight gain Diabetes Hyperlipidemia Movement disorders CV effects ```

Question 49

What percentage of drugs responsible for adverses are metabolised by polymorphic phase 1 metabolism enzymes

Answer 49

50%, of these 86% are metabolised by CYP450

Question 50

CYP450 1A2/3A4 are important in..

Answer 50

Metabolism of atypicals

Question 51

CYP2D6 metabolises many psychotropic drugs including

Answer 51

Haloperidol and risperidone

Question 52

How many variants of CYP2D6?

Answer 52

>70 variants | Classified into 4 phenotypes

Question 53

Poor metabolisers phenotype of CYP2D6

Answer 53

Lack functional enzyme Have 2 non-functioning copies No 2D6 Increase risk of adverses

Question 54

Intermediate metabolisers phenotype of CYP2D6

Answer 54

1 functional allele and 1 lower activity level allele = lower than normal metabolic rate of substrates Heterozygous

Question 55

Extensive metabolisers phenotype of CYP2D6

Answer 55

2 functional alleles | = normal metabolic rate

Question 56

Ultra metabolisers phenotype of CYP2D6

Answer 56

Gene duplication 3 or more copies of functional 2D6 activity Rapid metabolic rate Limited clinical response

Question 57

Phenotypes in ethnicities vary in CYP2D6..

Answer 57

5-10% Caucasians are PMs | 29% of North Eastern Africans and Middle Easteners are UMs

Question 58

CYP2D6 genotype 3*/5* has predicted phenotype..

Answer 58

PM

Question 59

CYP2C19 genotype *1/*1 has predicted phenotype..

Answer 59

EM/ normal

Question 60

Phenotype of CYPs may inform..

Answer 60

Prescription of someone with type 1 bipolar disorder

Question 61

FDA-approved what pharmacogenetic test for detecting CYP450s

Answer 61

AmpliChip

Question 62

AmpliChip can detect..

Answer 62

20 alleles for 2D6 3 alleles for 2C19 Identifies true UMs

Question 63

AmpliChip is useful when

Answer 63

In cases of atypicals where adverses (weight gain, sedation, motor problems and response are issues) e.g. risk of EPS from haloperidol is significantly increased in PMs for 2D6

Question 64

Problem with AmpliChip

Answer 64

Process needs development | Genotyping found to only prevent side effects in 5% of those given haloperidol

Question 65

Other factors contributing to response and tolerability ADME

Answer 65

``` Age Sex Ethnicicty Concomitant disease Liver/ kidney function Diet Smoking D-D interactons ```

Question 66

Consequences for drug development process

Answer 66

Less propensity for metabolism by polymorphic CYPs can be developed Target medication to patients most likely to receive a response and less likely to receive a SADR More effective and safer clinical trials Better post-marketing surveillance - prevent SADR in general population and sub-population that weren't picked up in clinical trial Loss of blockbuster drug, no one size fits all..